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Background: Medulloblastoma (MB) is the most common solid malignant pediatric brain neoplasm. Group 3 (G3) MB, particularly MYC amplified G3 MB, is the most aggressive subgroup with the highest frequency of children presenting with metastatic disease, and is associated with a poor prognosis. To further our understanding of the role of MSI1 in MYC amplified G3 MB, we performed an unbiased integrative analysis of eCLIP binding sites, with changes observed at the transcriptome, the translatome, and the proteome after shMSI1 inhibition. Methods: Primary human pediatric MBs, SU_MB002 and HD-MB03 were kind gifts from Dr. Yoon-Jae Cho (Harvard, MS) and Dr. Till Milde (Heidelberg) and cultured for in vitro and in vivo experiments. eCLIP, RNA-seq, Polysome-seq, and TMT-MS were completed as previously described. Results:MSI1 is overexpressed in G3 MB. shRNA Msi1 interference resulted in a reduction in tumour burden conferring a survival advantage to mice injected with shMSI1 G3MB cells. Robust ranked multiomic analysis (RRA) identified an unconventional gene set directly perturbed by MSI1 in G3 MB. Conclusions: Our robust unbiased integrative analysis revealed a distinct role for MSI1 in the maintenance of the stem cell state in G3 MB through post-transcriptional modification of multiple pathways including identification of unconventional targets such as HIPK1.
BACKGROUND: IGTS is a rare phenomenon of paradoxical germ cell tumor (GCT) growth during or following treatment despite normalization of tumor markers. We sought to evaluate the frequency, clinical characteristics and outcome of IGTS in patients in 21 North-American and Australian institutions. METHODS: Patients with IGTS diagnosed from 2000-2017 were retrospectively evaluated. RESULTS: Out of 739 GCT diagnoses, IGTS was identified in 33 patients (4.5%). IGTS occurred in 9/191 (4.7%) mixed-malignant GCTs, 4/22 (18.2%) immature teratomas (ITs), 3/472 (0.6%) germinomas/germinomas with mature teratoma, and in 17 secreting non-biopsied tumours. Median age at GCT diagnosis was 10.9 years (range 1.8-19.4). Male gender (84%) and pineal location (88%) predominated. Of 27 patients with elevated markers, median serum AFP and Beta-HCG were 70 ng/mL (range 9.2-932) and 44 IU/L (range 4.2-493), respectively. IGTS occurred at a median time of 2 months (range 0.5-32) from diagnosis, during chemotherapy in 85%, radiation in 3%, and after treatment completion in 12%. Surgical resection was attempted in all, leading to gross total resection in 76%. Most patients (79%) resumed GCT chemotherapy/radiation after surgery. At a median follow-up of 5.3 years (range 0.3-12), all but 2 patients are alive (1 succumbed to progressive disease, 1 to malignant transformation of GCT). CONCLUSION: IGTS occurred in less than 5% of patients with GCT and most commonly after initiation of chemotherapy. IGTS was more common in patients with IT-only on biopsy than with mixed-malignant GCT. Surgical resection is a principal treatment modality. Survival outcomes for patients who developed IGTS are favourable.
Person-centered geriatric care requires attention to the diversity of older patients. The looming ethnogeriatric imperative, when 40% of geriatric patients will be from a minority population, will require health care organizations and providers to meet elders’ unique cultural needs. These include meeting the Culturally and Linguistically Appropriate Standards (CLAS), especially providing language access for elders with limited English proficiency; developing cultural humility and confronting unconscious bias; knowing major health beliefs, special health risks, and the cohort experiences of elders of different populations; and using culturally appropriate assessment techniques, including eliciting elders’ explanatory models of their conditions. Older adults are also more likely to have low health literacy or to experience challenges obtaining, processing, or comprehending health information. As low health literacy has been linked to poor health outcomes, geriatric providers must develop skills to ensure they understand their patients and that their patients understand them
Objectives: One of the most prominent features of schizophrenia is relatively lower general cognitive ability (GCA). An emerging approach to understanding the roots of variation in GCA relies on network properties of the brain. In this multi-center study, we determined global characteristics of brain networks using graph theory and related these to GCA in healthy controls and individuals with schizophrenia. Methods: Participants (N=116 controls, 80 patients with schizophrenia) were recruited from four sites. GCA was represented by the first principal component of a large battery of neurocognitive tests. Graph metrics were derived from diffusion-weighted imaging. Results: The global metrics of longer characteristic path length and reduced overall connectivity predicted lower GCA across groups, and group differences were noted for both variables. Measures of clustering, efficiency, and modularity did not differ across groups or predict GCA. Follow-up analyses investigated three topological types of connectivity—connections among high degree “rich club” nodes, “feeder” connections to these rich club nodes, and “local” connections not involving the rich club. Rich club and local connectivity predicted performance across groups. In a subsample (N=101 controls, 56 patients), a genetic measure reflecting mutation load, based on rare copy number deletions, was associated with longer characteristic path length. Conclusions: Results highlight the importance of characteristic path lengths and rich club connectivity for GCA and provide no evidence for group differences in the relationships between graph metrics and GCA. (JINS, 2016, 22, 240–249)
Nanoscale superlattice-like (SLL) dielectric was employed to reduce the power consumption of the Phase-change random access memory (PCRAM) cells. In this study, we have simulated and found that the cells with the SLL dielectric have a higher peak temperature compared to that of the cells with the SiO2 dielectric after constant pulse activation, due to the interface scattering mechanism. Scaling of the SLL dielectric has resulted in higher peak temperatures, which can be even higher after material/structural modifications. Furthermore, the SLL dielectric has good material properties that enable the cells to have high endurance. This shows the effectiveness of the SLL dielectric for advanced memory applications.
To define the clinical and audiological features of normal-hearing tinnitus patients with spontaneous otoacoustic emissions, and to evaluate the role of spontaneous otoacoustic emissions in tinnitus generation.
Materials and methods:
Thirty-two patients with spontaneous otoacoustic emissions were compared with 29 patients without spontaneous otoacoustic emissions, regarding clinical and audiological aspects.
The mean age of the study group subjects was significantly lower, and they experienced the kindling effect less frequently than the control group. The mean tinnitus handicap inventory score of the study group was considerably higher than that of the controls, although the difference was not statistically significant. The study group had significantly quieter tinnitus, and higher transient evoked and distortion product otoacoustic emission responses, compared with the control group.
Normal-hearing tinnitus patients with spontaneous otoacoustic emissions have different clinical and audiological characteristics, compared with those without spontaneous otoacoustic emissions. Appropriate evaluation and treatment should be considered at an early stage in these patients.
The behaviour of fluid-particle acceleration in near-wall turbulent flows is investigated in numerically simulated turbulent channel flows at low to moderate Reynolds numbers, Reτ = 180~600). The acceleration is decomposed into pressure-gradient (irrotational) and viscous contributions (solenoidal acceleration) and the statistics of each component are analysed. In near-wall turbulent flows, the probability density function of acceleration is strongly dependent on the distance from the wall. Unexpectedly, the intermittency of acceleration is strongest in the viscous sublayer, where the acceleration flatness factor of O(100) is observed. It is shown that the centripetal acceleration around coherent vortical structures is an important source of the acceleration intermittency. We found sheet-like structures of strong solenoidal accelerations near the wall, which are associated with the background shear modified by the interaction between a streamwise vortex and the wall. We found that the acceleration Kolmogorov constant is a linear function of y+ in the log layer. The Reynolds number dependence of the acceleration statistics is investigated.
We aimed to evaluate a practical, computerised database for collection of patient-reported and clinical outcome data, introduced as a means of characterising our patient population and assessing the effect of our interventions.
A prospectively updated, computerised database was used to detail each patient's coded and structured diagnosis and clinical findings. Response to treatment was recorded using the Sino-Nasal Outcome Test 22 and changes in graded clinical examination findings.
Data for 770 patients were prospectively entered into the database. Patients were grouped diagnostically as follows: rhinitis (20.4 per cent), chronic rhinosinusitis (12.2 per cent), chronic rhinosinusitis with polyps (24.7 per cent), anatomical anomaly (22.7 per cent), epistaxis (3.4 per cent) and ‘other’ (18.4 per cent). Following initial medical intervention, the greatest improvement in the Sino-Nasal Outcome Test 22 score was seen in the chronic rhinosinusitis with polyps group (−11.3), followed by the rhinitis group (−6.1) and the chronic rhinosinusitis group (−5.4).
The tested rhinology database provides a simple, effective and practical tool for integrating the recording of clinical and patient-reported outcome measures during the out-patient visit. It enables characterisation of the patient population, and accurately monitors and records treatment responses.
This study used a prospective design and the technique of structural modelling to examine the complex interrelations between psychological factors, immune status and complications after major surgery.
Twenty-nine women scheduled for elective cholecystectomy were studied prospectively. Information regarding medical history, health practices, life stressors, and coping strategies was obtained two weeks prior to admission. At this initial meeting, as well as three days after surgery, and at one month follow-up immunological tests were performed and the level of psychological distress was assessed. The study additionally included measures of post-operative complications, and infections and negative effect during follow-up.
Pre-operative immune status emerged as a key variable exerting strong effects on subsequent immune function and, thereby producing significant, indirect effects on every recovery variable. Pre-operative distress was directly linked to increased mood disturbance at follow-up. Moreover, distress significantly influenced immune function both before and after surgery, which mediated a significant impact on most recovery variables. Active coping behaviour directly increased the risk of a complicated recovery.
The study demonstrated that distress-induced changes in immune functioning have clinical relevance. Overall, the present findings suggest that recovery from surgery is facilitated in patients with a well-functioning immune system, a low-level of pre-operative distress and a passive coping disposition.
Patch clamp recordings from ion channels often show periods of repetitive activity, known as bursts, which are noticeably separated from each other by periods of inactivity. Depending on the type of channel, such recordings may exhibit (conductance) levels between the closed (zero) level and the fully open level. Properties of bursts are less subject to problems that arise from recording than are properties for individual sojourns at different levels, and study of bursting behaviour provides important information about the finer structure of the underlying channel gating process. For a general finite state space continuous-time Markov chain model allowing one or more nonzero conductance levels, the present paper establishes results about the semi-Markov structure of a single burst and of a sequence of bursts, and uses this in a unified approach to properties of both theoretical and empirical bursts. The distribution and moments of particular burst properties, including the total charge transfer, the total sojourn time and the total number of visits to specified conductance levels during a burst, are derived. Various extensions are also described.
Strong rare earth (RE) emissions from Nd and Er implanted into MOCVD grown GaN were observed through photoluminescence (PL) with below bandgap excitation from an Ar+laser. Three well resolved manifolds of 4f lines from the crystal-field split 4F3/2 → 4I9/2, 4F3/2 → 4I11/2, and 4F3/2 → 4I13/2 transitions of Nd3+ were observed at low temperature at ˜0.98, ˜1.14, and ˜1.46 μm, respectively. The Er implanted GaN showed both the 4I13/2 → 4I15/2 Er3+ transition at ˜1.54 μm and the 4I11/2 → 4I15/2 Er3+ transition at ˜1.00 μm. The Er luminescence at ˜1.54 μm and Nd luminescence at ˜1.1 μm persisted to room temperature. Both Er and Nd implanted samples showed increasing RE3+ signal as annealing temperature increased from 700 to 1000 °C. The growth of new 4f crystal-field split-lines in the ˜1.54 μm 4I13/2 → 4I15/2 manifold as annealing temperature was increased to 1000 °C suggests multiple Er3+ radiative centers.
Electrical and optical measurements were performed on p-type GaAs implanted with 1013 Er ions/cm2 at an energy of 1 MeV. The samples were annealed at 650, 750, 850, or 900 °C for 15 seconds using the rapid thermal annealing technique. Although annealing at 650 °C was insufficient to recover measureable electrical conductivity in the implanted region, Er3+ 4f-4f emissions were still observed. Annealing at 750 TC produced a large concentration of hole traps at EV + 360 meV, and the most intense Er-related emissions at 1.54 μm. The two higher annealing temperatures returned the implanted region to the conductivity of the substrate but resulted in weak Er-related emissions. Two distinct Er-related centers were found, and they are believed to be the cause of the intense and weak emissions, an Er-interstitial and Er substituting for Ga, respectively.
A GI/G/r(x) store is considered with independently and identically distributed inputs occurring in a renewal process, with a general release rate r(·) depending on the content. The (pseudo) extinction time, or the content, just before inputs is a Markov process which can be represented by a random walk on and below a bent line; this results in an integral equation of the form gn+1(y) = ∫ l(y, w)gn(w) dw with l(y, w) a known conditional density function. An approximating solution is found using Hermite or modified Hermite polynomial expansions resulting in a Gram–Charlier or generalized Gram–Charlier representation, with the coefficients being determined by a matrix equation. Evaluation of the elements of the matrix involves two-dimensional numerical integration for which Gauss–Hermite–Laguerre integration is effective. A number of examples illustrate the quality of the approximating procedure against exact and simulated results.
This note considers a finite dam fed by independently and identically distributed (i.i.d.) inputs, being either (i) of at least size β (> 0) or (ii) negative exponentially distributed, occurring in a Poisson process. The instantaneous release rate may be a function r(·) of the content; additional and numerical results are given for the special case where r(x) = µxα (0 ≦ α<∞, 0 < µ <∞) is proportional to the αth power of the content. The basic method used in  for the special case r(x) = µx for obtaining the distribution of the number of steps and of the time to first overflowing is shown to carry over almost completely in case (i), but only partially so in case (ii).
This paper considers a finite dam with independently and identically distributed (i.i.d.) inputs occurring in a Poisson process; the special cases where the inputs are (i) deterministic and (ii) negative exponentially distributed are considered in detail. The instantaneous release trate is proportional to the content, i.e., there is an exponential fall in conten except when inputs occur. This model may arise in several other situations such as a geiger counter or integrated shot noise. The distribution of the number of inputs, and of the time, to first overflowing is obtained in terms of generating functions; in Case (i) the solution is obtained through recurrence relations involving iterated integrals which can be evaluated numerically, and in Case (ii) using a series solution of a second order differential equation. Numerical results, in particular for the first two moments, are obtained for various values of the parameters of the model, and compared with a large number of simulations. Some remarks are also made about the infinite dam.
This paper is concerned with negative binomial processes which are essentially mixed Poisson processes whose intensity parameter is given by the sum of squares of a finite number of independently and identically distributed Gaussian processes. A study is made of the distribution of the number of points of a k-dimensional negative binomial process in a compact subset of Rk, and in particular in the case where the underlying Gaussian processes are independent Ornstein-Uhlenbeck processes when more detailed results may be obtained.
In this paper we present a method for obtaining explicit results for some two-sided boundary problems involving sums of independent random variables with alternating distributions. We apply the method to finding the first passage time to either one of two finite barriers, and to some situations arising in queueing and dam theory. The results can be expressed in terms of a finite sum of simple repeated integrals (or sums) of known functions (cf. formulae (3.6)– (3.11)).
Several models for phage reproduction within a bacterium have recently been discussed by Steinberg and Stahl (1961), Gani (1962) and Ohlsen (1963); all are effectively birth-death type processes, with the first of these considering a single type of phage mutation. A detailed description of the biological processes involved may be found in Adams (1959), Weidel (1959), Sanders (1961) and Smith (1961). In this paper we shall consider some general models extending that of Steinberg and Stahl in which mutation may take place from normal a phages to mutant A phages.